Objective
This study aimed to evaluate the effect of oxygen therapy on the incidence of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography.
Background
CIN has been the third leading cause of hospital-acquired renal failure, accounting for 11% of cases. Patients with cardiac diseases are particularly at risk: 49% of CIN occurs after cardiac catheterization and coronary angioplasty in which repeated injections of contrast media are often required.
Patient and methods
We randomly assigned 200 consecutive patients who underwent elective coronary angiography to two groups: an oxygenation group, in which oxygen was administered through nasal cannula at a rate of 2 l/min from 15 min before the procedure until the end of the procedure (n = 100) and the control group (room air: n = 100). Arterial blood sample was drawn at the beginning of the procedure (coronary angiography) to estimate PaO2level. Baseline and follow-up serum creatinine was compared to diagnose CIN.
Results
A total of 200 patients were enrolled in the study. There were no significant differences as regards patient characteristics and risk factors for CIN. The PaO2at the baseline was significantly higher in the oxygen preconditioned group than in the control group (115.730 ± 15.774 vs. 84.140 ± 7.916 mmHg, P < 0.001). CIN occurred in 14 (7%) of 200 patients. The incidence of CIN was significantly lower in the oxygen preconditioning group than in the control group [3/100 (3%) vs. 11/100 (11%), P= 0.027], indicating that oxygen preconditioning concomitant with standard isotonic saline hydration suppressed CIN.
Conclusion
Oxygen preconditioning concomitant with standard isotonic saline hydration decreased the incidence of CIN in patients undergoing coronary angiography.

Contrast nephropathy is defined as a rise in the serum creatinine (SCr) level of at least 0.5 mg/dl within 48 h of contrast medium administration or an increase in SCr of more than 25% of the baseline level within 48 h of administration of the contrast agent [1].

The incidence of contrast-induced nephropathy (CIN) is variable and ranges from 5 to 50% in various series. A lower incidence is observed in patients with mild renal dysfunction. Patients with creatinine greater than 1.3 mg/dl, dehydration, diabetes mellitus (DM), and the concomitant use of nephrotoxic medications will have a higher incidence. Serious nephrotoxicity requiring dialysis, however, is rare and occurs in less than 1% of patients [2].

Contrast media (CM) induce nephropathy through different mechanisms leading to hypoxia and acute tubular necrosis [3].

Hence, we aimed to study the effect of oxygen therapy on the incidence of CIN by abolishing the resulted renal hypoxia.

Patients and Methods

The study was approved from the ethical commmittee of Faculty of Medicine Menoufia University and the patient gave an informed consent. This is a prospective randomized study that included 200 patients who were referred for coronary angiography at El Menoufia University Hospital from January 2013 to October 2013.

All study patients were subjected to the following after taking written consent: history taking focusing on risk factors (DM, anemia, hypotension, congestive heart failure (HF), nephrotoxic drugs before the procedure, and baseline SCr).

Half of the patients (100 patients) received oxygen therapy in the form of 2 l/min of pure oxygen through nasal cannula for 15 min before and during the procedure (coronary angiography). The other half (100 patient) underwent the procedure (coronary angiography) without receiving the oxygen therapy.

All patients received intravenous rehydration in the form of 3 ml/kg/h normal saline for 1 h before the procedure and 1 ml/kg/h normal saline for 6 h after it.

SCr level was measured 48 h after the procedure for detecting the occurrence of CIN, which is defined as an increase in SCr of more than 25% of the baseline level within 48 h of administration of the contrast agent [2].

Statistical analysis

Categorical variables (DM, etc.) were represented as percentage and the c2-test was used to detect the P valueContinuous variables (age, etc.) were presented as mean and SD and the t-test was used to detect the P valueFor analytic statistics a P value less than 0.05 was considered significant, P value less than 0.001 as highly significant, and P value more than 0.05 as nonsignificant.

We studied the effect of different risk factors on the incidence of CIN. There was a statistically significant difference as regards anemia (P = 0.016), DM (P = 0.005), history of nephrotoxic drug administration (P = 0.012), hypotension (P = 0.001), history of HF (P < 0.001), and amount of administered contrast (P = 0.006) and there were no statistically significant differences as regards age (P = 0.888) and baseline SCr (P = 0.221) [Table 3] and [Table 4].{Table 3}{Table 4}

PaO2 was higher in the oxygen preconditioned group than in the control group with a statistically significant difference (115.730 ± 15.774 vs. 84.140 ± 7.916) (P < 0.001 using t-test).

The incidence of CIN in the oxygen preconditioned group was 3% in comparison with 11% in the control group with a statistically significant difference (P = 0.027 using the c2-test) [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7].{Figure 1}{Figure 2}{Figure 3}{Figure 4}{Figure 5}{Figure 6}{Figure 7}

On comparing patients who developed CIN in the O2 group with those in the control group there was a statistically significant difference as regards anemia (P = 0.0405), DM (P = 0.0206), and history of nephrotoxic drugs administration (P = 0.030) and no statistically significant difference as regards hypotension (P = 0.8504), congestive HF (P = 0. 4745), age (P = 0.426), baseline SCr (P = 0.177), and amount of administered dye (P = 0.592) [Table 5] and [Table 6].{Table 5}{Table 6}

The effect of oxygen was highly significant on the state of SCr (P < 0.001) as it decreased in 49 patients in the O2 group versus 10 patients in the control group, increased in 35 patients in the O2 group versus 83 patients in the control group, and still stable in 16 patients the O2 group versus six patients in the control group.

The mean follow-up creatinine (after 48 h) for the O2 group was 0.982 versus 1.173 mg/dl for the control group with significant statistical difference (P < 0.001) [Table 7].{Table 7}

Discussion

CIN is defined as the impairment of renal function and is measured as either a 25% increase in SCr from baseline or 0.5 mg/dl (44 μmol/l) increase in absolute value, within 48–72 h of intravenous contrast administration [1].

However, SCr level is an insensitive measure of renal function. Moreover, SCr level is not an accurate reflection of glomerular filtration rate (GFR) as it is influenced by many factors, including muscle mass, sex, diet, liver function, age, and tubular secretion, which can result in an overstatement of GFR up to 20%, and hence serum cystatin C was used as a better marker for GFR compared with SCr [2]. Nevertheless, we use SCr changes to diagnose CIN.

Direct tubular toxicity [3] as well as hypoxic renal medullary injury [4] has been proposed as a mechanism for the pathogenesis of CIN.

Systemic effects of the contrast that may contribute to the decline in renal tissue oxygenation include the induction of pulmonary ventilation–perfusion mismatch [5], reduced cardiac output and renal perfusion pressure [6], rheological alterations of the blood [7], and a leftward shift of the oxygen–hemoglobin dissociation curve [8].

However, the greater part of the decline in renal parenchymal oxygenation is attributed to altered intrarenal balance of oxygen supply and demand.

CM administration is associated with an abrupt transient increase in glomerular filtration and urinary output [9]. This response is mediated in part by an increase in plasma volume and the release of natriuretic peptides in addition to the substantial osmotic load provided by many CM, which lead to enhanced solute delivery to the distal nephron, with the pursuant increase in oxygen consumption for tubular reabsorption [10].

Liss et al. [11] and subsequently Sekiguchi et al. [12] recorded papillary blood flow with laser-Doppler probes after the exposure of the papilla by the dissection of the renal pelvis. Using video microscopy of transilluminated papillary vasa recta and the dual-window cross-correlation technique, they also documented near cessation of red blood cell movement in papillary blood vessels, associated with red cell aggregation [11].

Altogether, these findings indicate that CM-induced accentuation of inner medullary hypoxia is mediated to a large extent by a decline in regional blood flow and oxygen supply.

In our study we evaluated the protective effect of O2 therapy when added to standard protective measure by normal saline hydration using two groups of patients undergoing coronary angiography.

The clinical and demographic data (age, sex, and risk factors) were statistically nonsignificant between groups.

We found that with higher PaO2 the incidence of CIN was significantly lower in the oxygen preconditioned group than in the control group [3/100 (3%) vs. 11/100 (11%)] (P = 0.027 using the c2-test).

This is in accordance with the findings of Sekiguchi et al. [12], who found that the incidence of CIN was significantly lower in the oxygen preconditioned group than in the control group [1/174 (0.6%) vs. 9/175 (5.1%) P= 0.01].

An increase in renal blood flow with oxygen could be mediated by several mechanisms, including a rise in cardiac output or carbon dioxide tension, alterations in circulating hormones acting on the kidney, or a direct action on the renal vasculature [14].

When evaluating each risk factor separately we found the following.

Diabetes mellitus

The incidence of CIN was higher in diabetic patients than in nondiabetic patients with a statistically significant difference (P = 0.005), which is in accordance with the findings of Lindsay [15] and Nikolsky [16].

The incidence of CIN in diabetic patients in the O2 group was 3.22% in comparison with 28.57% in diabetic patients in the control group with a statistically significant difference (P = 0.006), which may be attributed the fact that diabetes leads to enhanced distal tubular reabsorption due to increased GFR, osmotic diuresis, and increased tubular ion pump mass. At the same time, nitrovasodilation is characteristically altered. Not surprisingly, basal outer medullary PO2 is significantly reduced in diabetic animals [17], and medullary post-transcriptional expression of hypoxia-inducible factors is detected shortly after the induction of experimental diabetes [18].

On comparing the incidence of CIN in diabetic patients on O2 therapy and nondiabetic patients, the incidence was nearly the same (3.22 vs. 3.45%), indicating that O2 therapy nearly abolished the risk effect of diabetes.

Nephrotoxic drugs

The incidence of CIN was higher in patients on nephrotoxic drugs than in patients not on nephrotoxic drugs with a statistically significant difference (P = 0.012), which is in accordance with the findings of Alamartine et al. [19].

We found that CIN in patients on nephrotoxic drugs in the O2 group was 3.8% in comparison with 18.54% in the control group with a statistically significant difference (P = 0.030). These drugs affect renal hemodynamics through a decrease in efferent arteriolar tone and intraglomerular capillary pressure [9].

On comparing the incidence of CIN in patients on nephrotoxic drugs who received O2 therapy and patients not on nephrotoxic drugs the incidence was nearly the same (3.8 vs. 2.17%) indicating that O2 therapy nearly abolished the risk effect of nephrotoxic drugs.

Anemia

The incidence of CIN was higher in anemic patients than in nonanemic patients with a statistically significant difference (P = 0.016). This is in accordance with the findings of Nikolsky et al. [16], who found that a low baseline hematocrit is a predictor of CIN in patients undergoing PCI.

We found that the incidence of CIN in anemic patients in the O2 group was 3.1% in comparison with 22.22% in the control group with a statistically significant difference (P = 0.020).

On comparing the incidence of CIN in anemic patients who received O2 therapy and nonanemic patients, the incidence was nearly the same (3.1 vs. 3.79%) indicating that O2 therapy nearly abolished the risk effect of anemia.

Pre-existing renal disease

Baseline SCr did not affect the incidence of CIN (P = 0.221). This is in disagreement with the findings of Rihal et al. [21] and many others, which may be attributed to the fact that they used a cutoff point of more than 1.5 mg/dl to diagnose pre-existing renal disease, which was not found in our patients except for two of them.

Pre-existing renal disease is associated with hypertrophy of remnant nephrons and with structurally altered medullary microcirculation [22]. We found that the mean baseline SCr in CIN patients in the O2 group (0.766 mg/dl) was lower than the mean baseline SCr in CIN patients in the control group (0.967 mg/dl) yet with no statistically significant difference (P = 0.177); this may be attributed to the small study sample (three patients vs. 11 patients).

Age

We found that the mean age was 56.613 years in the negative group of CIN and 57 in the positive group of CIN with no statistically significant difference in age as a risk factor (P = 0.888) using t-test. This is contradictory to the findings of Mehran et al. and Dangas et al. [21],[22]; this happened because in our study groups the age does not exceed 75 years, which was the cutoff point in these studies.

We found that the mean age in CIN patients in the O2 group was 52 years in comparison with 58.363 years in the control group with no statistically significant difference (P = 0.426). The oxygen effect was nonsignificant as the study sample was small (three patients vs. 11 patients).

History of heart failure

The incidence of CIN in patients with a history of HF was higher than the incidence of CIN in patients without a history of HF with a statistically significant difference (P < 0.001) using the c2-test, which is in accordance with the findings of Nikolsky et al. [16].

However, the incidence of CIN in patients with a history of HF in the O2 group was (20%) lower than the incidence of CIN in patients with a history of HF in the control group (50%). This can be attributed to the fact that HF is characterized by effective volume depletion and increased neurohumoral vasoconstrictive stimuli that might compromise medullary oxygenation [22]. However, there was no statistically significant difference (P = 0.688) as the study sample was small (five patients vs. six patients).

On comparing the incidence of CIN in patients with a history of HF who received O2 therapy and patients without a history of HF, the incidence was higher in patients with a history of HF (20 vs. 4.76%) as the study samples were not the same size.

Hypotension

The incidence of CIN in patients with hypotension was higher than the incidence of CIN in nonhypotensive patients with a statistically significant difference (P = 0.001) using the c2-test, which is in accordance with the findings of Lindsay et al. [15].

Although the incidence of CIN in hypotensive patients in the O2 group was 50% in comparison with 66% in the control group, there was no statistically significant difference (P = 0.850) as the study sample was small (two patients vs. three patients).

On comparing the incidence of CIN in hypotensive patients who received O2 therapy and nonhypotensive patients, the incidence was higher in patients with hypotension (50 vs. 2.17%) as the study sample was not the same size.

Amount of administered dye

We found that the mean amount of administered contrast was 101 ml in the negative group for CIN and 135 ml in the positive group for CIN with a statistically significant difference (P = 0.006), which is in accordance with many studies that have shown that the incidence of CIN is related to the amount of the administered dye [23],[24],[25].

We also found that the mean amount of administered dye in CIN patients in the O2 group was 110.6 ml in comparison with 128.18 ml in the control group with no statistically significant difference (P = 0.592) as the study sample was small (three patients vs. 11 patients).

The difference in the state of creatinine level between the two groups after 48 h was as follows:

It increased in 35 patients in the O2 group in comparison with 83 patients in the control groupIt was stable in 16 patients in the O2 group in comparison with seven patients in the control groupIt decreased in 49 patients in the O2 group in comparison with 10 patients in the control group.

There was a statistically significant difference in state of creatinine (P < 0.001) using the c2-test.

The mean follow-up creatinine (after 48 h) for the oxygen preconditioned group was 0.982 ± 0.214 versus 1.173 ± 0.332 mg/dl for the control group with significant statistical difference (P < 0.001).

Conclusion

Oxygen preconditioning concomitant with standard isotonic saline hydration decreased the incidence of CIN, especially in diabetic, anemic, and in patients on nephrotoxic drugs.